Project 2 The objective of the Project 2 is to significantly improve our understanding of complex genetic regulation of human aging, and investigate relevance of genetic factors influencing physiological aging changes in body to risks of major diseases and to longevity. To address this objective, we will identify genetic variants which individually and jointly influence markers of physiologicalaging specified in this project, using sets of longitudinal human data available through dbGaP. A special emphasis of the research will be on pleiotropic effects (both antagonistic and non-antagonistic) of a genotype on different traits, and on one trait at different ages. Specific Aims: 1) Evaluate individual and additive polygenic influence of SNPs on markers of physiological aging. For this we will conduct a hypothesis-free GWAS of aging phenotypes specified in this project and evaluate individual and joint (additive) effects of selected genetic variants on the aging phenotypes, using polygenic risk scores; 2) Investigate pleiotropic (both antagonistic and non-antagonistic) effects of individual SNPs and polygenic scores evaluated in Aim 1 on aging traits specified in this project, and on health and longevity traits evaluated in two other projects. We will test hypotheses about the pleiotropic (including trade-offs)influence of a genotype on: (i) different traits; and (ii) one trait at different ages. 3) Investigate functional relationships among genes/regulatory elements linked to SNPs detected in Aim1. For this, we will use online resources and tools for SNPs/genes/proteins annotating, gene-to-function and pathway analysis, to specify biological functions most relevant to the detected genes, and investigate their involvement in known aging pathways and networks. 4) Evaluate epistatic genetic influence on markers of physiological aging. We will select subsets of SNPs for their: a) pleiotropic effects on aging phenotypes detected in Aim 2; b) relation to genes involved in similar biological functions in Aim 3; c) involvement in aging-related pathways. For these subsets of SNPs, we will evaluate epistatic genetic effects on aging phenotypes.Results of this study will significantly improve our understanding of genetic regulation of aging, and its role in health and longevity.